Neuroscience Letters 403 (2006) 195–200 Development of baclofen tolerance in a rat model of chronic spasticity and rigidity Michael P. Hefferan a,∗ , Tatsuya Fuchigami a,b , Martin Marsala a a Anesthesiology Research Laboratory, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0818, United States b Department of Anesthesiology, University of the Ryukyus, Okinawa, Japan Received 27 February 2006; received in revised form 18 April 2006; accepted 27 April 2006 Abstract Systemic or spinal treatment with baclofen has been associated with the development of tolerance in patients with chronic spasticity. In the present study, we used a rat model of spinal ischemia-induced spasticity to characterize the development of baclofen tolerance after chronic intrathecal (i.t.) baclofen infusion. Following the induction of spinal ischemia and the development of behavioral spasticity, animals were implanted with i.t. catheters connected to osmotic pumps to continuously infuse baclofen (1.0 g/0.5 l/h). Hindleg peripheral muscle resistance (PMR) was measured periodically after initiation of chronic infusion and after bolus i.t. baclofen injection (1.0 g). Peripheral muscle resistance was significantly decreased at the onset of baclofen infusion, however, after 5–7 days of infusion a progressive return of spasticity was noted, where baseline PMR values returned to preinfusion levels. At the same time, the efficacy of bolus i.t. baclofen treatment also decreased, where after 5 days of baclofen infusion 1.0 g (i.t.) baclofen only reduced PMR by 10% (compared to 40–50% preinfusion). Baclofen efficacy progressively returned once continuous infusion was stopped. These data demonstrate that transient spinal ischemia leads to the development of spasticity which is sensitive to spinal baclofen. Chronic i.t. infusion leads to a progressive development of tolerance. This model offers potential to study tolerance mechanisms after spinal injury, and aid in drug discovery for use in baclofen-tolerant patients. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Spasticity; Rat; Spinal cord ischemia; Baclofen; Tolerance; GABA B receptor Spasticity and rigidity are frequent neurological deficits asso- ciated with traumatic or ischemic injury to the brain or spinal cord, as well as neurological diseases such as multiple sclero- sis, cerebral palsy, and Parkinson’s disease [3,6,8]. Spasticity is characterized by muscle hypertonia and displays increased resis- tance to externally imposed movement with increasing speed of stretch [18,36], while rigidity is defined as continuous involun- tary sustained muscle contraction with a constant degree of resis- tance when the muscle is stretched at different velocities [26]. Despite diverse etiologies, a common denominator is increased peripheral muscle tone secondary to exaggerated -motoneuron activity. Current clinical strategies to control spasticity and rigid- ity include surgical approaches like myelotomies and dorsal or ventral rhizotomies [20], and/or systemic or spinal treatment ∗ Corresponding author. Tel.: +1 619 543 3597; fax: +1 619 543 6070. E-mail address: mhefferan@ucsd.ed (M.P. Hefferan). with various pharmacological agents like tizanidine, diazepam, dantrolene, and baclofen. Baclofen is a potent agonist at the GABA B receptor and is presently a frequently used clinical drug in the treatment of spasticity and rigidity [28]. Like other GPCRs (e.g. opioid receptors), experimental and clinical data show that tolerance develops with continued GABA B receptor activation [10,12]. In clinical studies, for example, it has been shown that patients that use chronic baclofen therapy to control spasticity often require a 2–4-fold dose increase to achieve a satisfactory control of spas- ticity during the first 12–36 months after treatment initiation [7,29]. Studies of chronic baclofen treatment in naive animals have produced a number of similar reports of tolerance (e.g. refs. [22,39]). However, to the best of our knowledge there are no well-defined baclofen tolerance studies which employ a rodent spinal injury model of spasticity. Previous experimental studies have demonstrated the devel- opment of prominent rigidity and spasticity after transient spinal cord ischemia using the rat or cat spinal ischemia models [14,37]. 0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.04.048